Methicillin-Resistant Staphylococcus aureus (MRSA) produces significant morbidity and mortality among a large and growing population of hospitalized and chronically ill patients in the US. As invasive disease due to MRSA continues to rise, there is an urgent need to critically evaluate prevention strategies. The most effective strategies are likely to be those that not only decrease healthcare-associated transmission, but also reduce carriage among people who already harbor this pathogen. While screening protocols and decolonization regimens exist, guidance is lacking on which groups would benefit most from these interventions. We will quantify the comparative effectiveness of screening and decolonization strategies targeting well-defined high risk groups in the hospital and immediate post-discharge period. We will assess the impact of these strategies on invasive MRSA disease, including the amount of MRSA disease prevented by each strategy, the cost per disease averted, and the trade offs of engendering resistance to decolonization agents. Importantly, we will assess the ability of these strategies to not only reduce the risk of MRSA disease among individual patients, but also to reduce overall prevalence of MRSA in the population, including the possibility of elimination. Our findings will inform decision-making at individual health care facilities as well as county and state public health departments related to decolonization initiatives. PUBLIC HEALTH RELEVANCE: Methicillin-Resistant Staphylococcus aureus (MRSA) infections affect a large and growing portion of hospitalized or chronically ill patients in the US. There are effective methods to clear (decolonize) MRSA from those who harbor it, but it is not known which patient groups would benefit most from decolonization strategies and comprehensive costs have not been formally assessed. Our investigation will compare the impact and cost of screening and decolonizing various high risk groups in the hospital and immediate post-discharge period to reduce MRSA disease, and will inform decision-making at individual hospitals as well as public health policies related to decolonization initiatives.